Clinical research
European Heart Journal (2007) 28, 3012–3019
doi:10.1093/eurheartj/ehm489
Coronary heart disease
Quantitative relationship between resting heart rate
reduction and magnitude of clinical beneﬁts in
post-myocardial infarction: a meta-regression
of randomized clinical trials
Michel Cucherat
´ de me
´decine Laennec, EA3736—Universite
´ Lyon 1, 11 rue Guillaume Paradin, 69008 Lyon France
Faculte
Received 12 June 2007; revised 13 September 2007; accepted 26 September 2007; online publish-ahead-of-print 2 November 2007
KEYWORDS
Meta-regression;
Resting heart rate reduction;
Beta-blockers;
Calcium channel blockers;
Meta-analysis;
Mortality
Introduction
Epidemiological studies suggest that lower resting heart
rate (HR) is associated with decreased cardiovascular and
all-cause mortality.1–9 HR has also been reported to be an
independent predictor of bad outcome after myocardial
infarction (MI)10,11 and a determinant of infarct size in
acute MI.12,13
A relationship between the resting HR reduction and the
mortality has also been observed in post-MI patients with
beta-blockers. In the Norwegian timolol study,13 logistic
regression analysis of the total death relative to the HR at 1
month after the start of treatment (with timolol or placebo)
remove the difference in outcome observed between the
timolol group and the placebo group. On the basis of the
results of 10 randomized controlled trials, Kjekshus14 had
observed that a correlation may exist between betablocker-induced reduction in resting HR and reduction in
total mortality. So a growing body of evidence also suggests
that pharmacological reduction in resting HR could decrease
morbidity and mortality in cardiovascular patients.10
Corresponding author. Tel: þ33 4 78 78 57 71; fax: þ33 4 78 77 69 17.
E-mail address: [email protected]
We sought to address this issue by meta-regression.
Meta-regression aims to investigate whether particular
covariates (potential effect modiﬁer) explain any of the
difference in treatment effects between multiple studies.15
A meta-regression was performed to determine to which
extent resting HR reduction induced by the various drugs
modifying HR affects the reduction of mortality and morbidity
observed in randomized placebo-controlled trials with these
drugs in post-MI.
Methods
The meta-regression was performed according to pre-deﬁned selection criteria for trial search and data analysis. QUOROM standards
were followed16 during all phases of the design and implementation
of this meta-regression.
Study identiﬁcation
I identiﬁed relevant published and unpublished unconfounded randomized trials that compared beta-blockers and calcium blockers
with placebo in post MI. I searched electronic databases (PubMed,
Embase) from 1966 to 1 January 2006 and the Cochrane Controlled
Trials Register (CENTRAL Issue 4, 2005). The broad strategy
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2007.
For permissions please email: [email protected].
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Aims The impact on mortality outcomes of beta-blockers and calcium blockers in post-myocardial
infarction (MI) has been suggested to be related to resting heart rate (HR) reduction. A meta-regression
of randomized clinical trials was carried out to assess this relationship using weighted meta-regression
of logarithm of odds ratio against absolute HR reduction.
Methods and results Twenty-ﬁve controlled randomized trials (21 with beta-blockers and four with
calcium channel blockers) involving a total of 30 904 patients meet eligibility criteria, but only 17 documented changes in resting HR (14 with beta-blockers and three with calcium channel blockers).
A statistically signiﬁcant relationship was found between resting HR reduction and the clinical beneﬁt
including reduction in cardiac death (P , 0.001), all-cause death (P ¼ 0.008), sudden death (P ¼ 0.015),
and non-fatal MI recurrence (P ¼ 0.024). Each 10 b.p.m. reduction in the HR is estimated to reduce the
relative risk of cardiac death by 30%.
Conclusion The meta-regression of the randomized clinical trials strongly suggest that the beneﬁcial
effect of beta-blockers and calcium channel blockers in post-MI patients is proportionally related to
resting HR reduction. Furthermore, the absence of residual heterogeneity indicated that resting HR
reduction could be a major determinant of the clinical beneﬁt.
Relationship between resting HR and magnitude of clinical beneﬁts
3013
described by Haynes17 was used for PubMed (search strategies are
described in the Supplementary material online).
I also reviewed the bibliographic references of the retrieved
studies, review and meta-analysis articles obtained from the
initial search. Conference proceedings of the following conferences
were hand searched: AHA, ACC, ESC from 1995 to 2005.
I also searched the WEB with the same keywords and trial registers (www.clinicaltrialresults.org and ISRCTN register).
I included trials published only in abstract form, to limit the inﬂuence of possible publication bias.
As a complementary analysis (planned in the protocol), we performed also the meta-regression using the relative risk. Publication
bias was assessed graphically using a funnel plot of the logarithm of
effect size vs. the standard error for each trial.
The meta-regression methods were implemented with the R software.22 The code was validated with running examples reported in
the methodological papers.
Statistical test were two-tailed with P , 0.05 chosen at the level
of signiﬁcance.
Study selection
I assessed all potentially relevant published articles and abstracts
for inclusion. To be included, trials had to meet the following criteria: (i) randomized placebo controlled (with or without allocation
concealment); (ii) double-blind design; (iii) with ,10% attrition; (iv)
patient followed-up for 1 year or more. Trials initially planned for 1
year follow-up or more but stopped prematurely for efﬁcacy reasons
were also considered; (v) patients with a history of MI regardless of
the period of treatment initiation. Trials with intravenous treatment
initiated during the acute phase of MI were also included; (vi) trials
had to be conducted with a beta-blocker, including those with
partial beta-1 agonist activity or with a calcium channel blocker.
Data collection and assessment of quality
Study selection
The process of study selection is outlined in Figures 1 and 2.
After selection, 21 trials with beta-blockers were included
and nine excluded, whereas four trials with calcium
channel blockers were included and 15 excluded. The
more frequent reason for exclusion was an insufﬁcient
follow-up duration of ,1 year. (The lists of excluded trials
are given in the Supplementary material online.) Resting
HR reduction was reported in 14 of the 21 trials with betablockers and in three of the four trials with calcium
channel blockers giving a total of 17 studies applicable for
the meta-regression.
The data concerning the HR reduction being not available
for all trials, we undertook a subgroup meta-analysis to
compare trials reporting HR reduction to the others in
Statistical methods
An initial robust analysis was performed to search if a relationship
between resting HR reduction and clinical beneﬁt exists. Clinical
beneﬁt refers to the estimation of the treatment effect on the clinically relevant endpoints of mortality and morbidity. Odds ratio
between the active treatment and placebo group was used to estimate the clinical beneﬁt on these endpoints. The trials were split in
three subgroups according to according to tertiles of HR reduction.
For each variable of clinical beneﬁt, a pooled odds ratio was calculated in every subgroup of resting HR reduction using a ﬁxed model,
given an estimate of the effect of treatment for the higher, average
and lower resting HR reductions. Then the three estimates were
compared with the x2 test for trend.19
In the second step, the analysis used a weighted meta-regression
by the inverse of variance,15,20 modelling the logarithm of odds ratio
as a linear function of the absolute resting HR reduction. In this
meta-regression, we used additive component of residual heterogeneity in order to take into account the diversity between trials
regarding drugs, regimen and patients. Restricted maximum
likelihood (REML) estimators were used.21 See online supplementary
data for model details.
Slope estimates were used to predict the relative risk reduction
potentially induced by 10 b.p.m. reduction in resting HR.
The robustness of the relationship was tested by sensitivity analyses where REML estimates were computed after exclusion of
trials with the lowest and largest resting HR reduction (one each
time). Subgroup analyses were planned to explore separately betablockers and calcium blockers.
Figure 1 Process of beta-blockers trials selection.
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All qualifying trials were assessed for adequate blinding of randomization, completeness of follow-up, and description of withdrawals using Jadad score.18
The absolute HR reduction was calculated by subtracting the
mean change from baseline observed in the placebo group from
the corresponding change observed in the active treatment group.
Changes in resting HR were determined between baseline resting
HR and resting HR after about 1 month on treatment, the exact
time of measure varying across trials. One month is the best compromise between the stabilization of the HR reduction and the
number of patients at risk and under treatment. Over this time,
occurrence of death and withdrawals decreased the number of
patients contributing towards the HR mean.
Results
3014
M. Cucherat
Effects of resting heart rate reduction
on clinical beneﬁt
Process of calcium channel blockers trials selection.
terms of treatment effects using the relative risk and a ﬁxed
effect model. No statistically signiﬁcant heterogeneity was
found between trials reporting the HR reduction value and
those not reporting this data.
Included trials
Beta-blockers and calcium channel blockers used in analysed
trials are shown in Table 1.
Inclusion criteria of all the trials speciﬁed that enrolled
patients had deﬁnite or suspected MI. Depending of the protocol of the trial, MI was diagnosed using clinical, electrical
signs and enzyme elevation (alone or in combination). The
enzymatic deﬁnition of MI varied across time and therefore
across the trials.
Beta-blockers trials were quite well conducted with
random allocation of treatment, masking of treatment
assignment, and patient follow-up rates of .95% except
for one trial (Wilhelmsson 1974 in which 7% of patients
were lost to follow-up). However, six trials had a Jadad
score less than 4, mainly due to insufﬁcient description of
randomization or double-blind, preventing the evaluation
of their appropriateness (allocation concealment in particular) or due to absence of withdrawals description. The
calcium channel blockers trials were also well conducted
and obtained all a Jadad score of 4 or 5.
Discussion
The present meta-regression shows a relationship between
the clinical beneﬁt and the resting HR reduction observed
with drugs modifying HR in post-MI patients. These ﬁndings
provide ﬁrm evidence that the clinical beneﬁt on cardiac
death, all-cause mortality, sudden death and non-fatal
recurrence of MI is proportional to the extent of resting
HR reduction.
For all these endpoints, the residual heterogeneity is estimated at zero, showing that the differences between trials
can be completely explained by resting HR reduction and
within-trial variability (sampling ﬂuctuations). This result is
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Figure 2
According to the availability of resting HR reduction and
endpoints data, 16 trials contributed to the meta-regression
for all-cause death, 12 for cardiac death, 7 for cardiovascular death, 13 for non-fatal MI recurrence and 6 for sudden
death.
Subgroups analysis by resting HR reduction tertiles
(Table 2 and Figures 3–6) showed that larger resting HR
reduction, compared with lower resting HR reduction,
were associated with an increased mortality reduction for
cardiac death (P ¼ 0.0015), all-cause death (P ¼ 0.017)
and sudden death (P ¼ 0.005). Similar relationship was
found for non-fatal MI recurrence (P ¼ 0.033). No signiﬁcant
relationship was found between resting HR reduction and
the treatment effect on cardiovascular deaths (P ¼ 0.09)
and on fatal and non-fatal MI (P ¼ 0.36). Cardiac events
were available in only three trials and did not allow any
reliable estimate of the relationship.
These results were all conﬁrmed by the meta-regression
(Table 2 and Figures 3–6) which showed the same type of
relationship.
No residual heterogeneity was detected, except for the
cardiovascular death where a marginal heterogeneity
appeared.
In the sensitivity analysis, the results for cardiac death
remained statistically signiﬁcant after the exclusion of
trials with highest or lowest resting HR reduction. For allcause mortality, sudden death, and recurrence of MI,
results remain signiﬁcant after removing the trial with the
smallest resting HR reduction. Results on the same endpoints
became statistically non-signiﬁcant after removing the trial
with the largest resting HR reduction but the results overall
remain qualitatively unchanged.
The meta-regression using log-relative risk (in place of log
odds ratio) led to very similar results (Table 3).
When analysis is restricted to the beta-blockers trials, a
statistically signiﬁcant relationship was found between HR
reduction and log odds ratio for cardiac death (P ¼ 0.02,
meta-regression slope¼0.039), sudden death (P , 0.01)
and non-fatal MI recurrence (P , 0.01). A similar but
non-statistically signiﬁcant relationship (P ¼ 0.17, metaregression slope¼0.21) was found with all-cause mortality.
Given the small number of available data (3 points),
meta-regression restricted to the calcium blocker trials
was not performed.
Funnel plots did not suggest the possibility of publication
bias.
Trial
Studied
treatment
HR at
baseline
Absolute HR
change
Age, mean
(years)
Female
(%)
B1 Andersen et al.30
B2 APSI31
B3 Aronow et al.32
B4 Australian and
Swedish Study33
B5 Baber et al.34
B6 Basu et al.35
Alprenolol
Acebutolol
Propranolol
Pindolol
NA
82.8/81.8
NA
77.9/76.8
NA
28.8
NA
25
NA
NA
81
58
NA
27
70
17
Propranolol
Carvedilol
81.3/81.9
NA
213
213.5
55
60
B7 BHAT36–38
B8 EIS39,40
B9 Hansteen et al.19
B10 Hjalmarson
et al.41
B11 Julian et al.42
B12 LIT Research
Group43
B13 Manger Cats
et al.44
B14 Multicentre
international45
B15 Norwegian
Multicentre Study
Group46
B16 Rehnqvist
et al.47
B17 Salathia et al.48
B18 Schwartz et al.
(high risk and low
risk)49
B19 Taylor et al.50
B20 Wilcox et al.51
B21 Wilhelmsson
et al.52
Calcium blockers
Propranolol
Oxprenolol
Propranolol
Metoprolol
76.2/75.7
73.5/74.2
81.5/78.7
NA
28
28
214
213
Sotalol
Metoprolol
76.4/77.3
79/79
215.8
NA
55
55
NA
40–74
(range)
55
58
Metoprolol
NA
NA
Practolol
76.8/77.2
Timolol
n (treated/
control)
Follow-up
duration (mean)
Attrition,
n (%)
Inclusion
period
Jadad’s
score
238/242
298/309
79/79
263/266
About 1 year
318 days
1 year
2 years
0
0
Unclear
Unclear
March 1976–December 1978
April 1987–September 1988
NA
February 1978–January 1980
3
5
2
4
15
23
355/365
77/74
9 months
6 months
Unclear
5 (3.31%)
1
5
36
29
31
35
1916/1921
858/883
278/282
698/697
25 months
1 year
1 year
2 yearsa
12 (0.3%)
Unclear
0
1.60%
NA
February 1992–September
1994
June 1978–October 1980
July 1979–July 1981
December 1977–July 1980
June 1981–January 1981
26
25
873/583
1195/1200
12 months
18 months
0
0.20%
January 1978–August 1980
August 1979–April 1982
4
5
NA
NA
273/280
1 year
NA
NA
3
29
55
36
1533/1520
3.40%
NA
5
74.4/74.3
218
61
38
945/939
12 months, up to 24
months
17 months
Unclear
January 1978–October 1979
4
Metoprolol
NA
NA
NA
NA
154/147
36 months
NA
NA
2
Metoprolol
Oxprenolol
NA
NA
NA
NA
NA
NA
46
NA
416/384
485/488
1 year
22 months (at least
6 months)
0.50%
NA
NA
NA
5
4
Oxprenolol
Propranolol
Alprenolol
76/77
79.5/80
NA
26
217
26
51
NA
NA
NA
28
NA
632/471
259/129
114/116
48 months
1 year
2 years
Unclear
0
(16) 7%
1973
NA
January 68–
4
5
3
C1 MDPIT et al.53
Diltiazem
71/72
23
48
20
1234/1232
3.20%
February 1983–June 1986
5
C2 CRIS54
C3 DAVIT II55
C4 SPRINT I56
Verapamil SR
Verapamil
Nifedipine
73/74
75/75
76.9/77.4
22
26
NA
55
NA
58
9
20
15
531/542
878/897
1130/1146
25 months (at least
12 months)
23.5 months
16 months
1 year
5 (0.47%)
NA
NA
1985–87
February 1985–
August 1981–July 1983
5
4
4
Beta-blockers
In the Go
¨teborg Metoprolol Study (B10), the double blind and placebo-controlled study lasted for 3 months. After that all patients were given open treatment with metoprolol and outcome was reported after 2 years.
3015
a
5
4
5
5
Relationship between resting HR and magnitude of clinical beneﬁts
Table 1 Characteristics of the trials included in the meta-regression
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3016
M. Cucherat
Table 2 Result summary of the analysis by subgroup and meta-regression
Endpoint
Number of
trials with
sufﬁcient
data
Subgroup
analysis by HR
reduction
tertile, P-value
for trend
Meta-regression
slope
Meta-regression,
P-value for slope
Residual
heterogeneity
Per cent reduction
in odds ratio for 10
and 15 b.p.m.
reduction in
resting HRa
All-cause death
Cardiac death
Cardiovascular deathd
Sudden death
Non-fatal MI recurrence
Fatal and non-fatal MI
Cardiac event (fatal and
non-fatal)
16
12
7
6
12
6
3
0.017
0.002
0.090
0.005
0.033
0.360
—
20.0249
20.0396
20.0204
20.0531
20.0243
0.00227
0.008b
,0.001c
0.550
0.015b
0.024b
0.960
—
0
0
0.0891
0
0
—
—
22/31
33/45
—
41/55
22/31
—
—
a
Per cent reduction in odds ratio are obtained by the exponential of the meta-regression slope.
Robustness result remains statistically signiﬁcant only after removal of the lowest HR reduction. The removal of the largest HR implies a NS result.
Robustness result remains statistically signiﬁcant after removal of the trial with the largest HR reduction or those with the smallest.
d
Cardiovascular deaths add to cardiac deaths vascular deaths and strokes.
b
c
Figure 4 By tertiles subgroup analysis and meta-regression for cardiac death. Odds ratios represented are comparing odds between the active treatment and
placebo group.
compatible with the assumption that the resting HR reduction
explains all the beneﬁt of these drugs. From this
meta-regression, there is no evidence of a drug/class speciﬁc
part in the beneﬁt. The lack of mortality reduction observed
with calcium antagonists could be totally explained by the
absence of resting HR reduction with the tested drugs
without need to take into account a speciﬁcity of the
calcium blockers. After adjustment on resting HR reduction,
there is no residual heterogeneity to be explained by other
factors between the trials. Thus, resting HR reduction
appears to be the major determinant of the clinical beneﬁt
induced by the drugs modifying resting HR in post MI patients.
For cardiovascular deaths, no statistically signiﬁcant
relationship was found most probably due to the small
number of trials available for this endpoint, seven in place of
12 for cardiac deaths. The value of the slope for this endpoint
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Figure 3 By tertiles subgroup analysis and meta-regression for all-cause death. Odds ratios represented are comparing odds between the active treatment and
placebo group.
Relationship between resting HR and magnitude of clinical beneﬁts
3017
Figure 5 By tertiles subgroup analysis and meta-regression for sudden death. Odds ratios represented are comparing odds between the active treatment and
placebo group. There were no data available for sudden death in the calcium blockers trials.
Table 3 Comparison of the results given by the meta-regression with the odds ratio and the relative risk
Endpoint
All-cause death
Cardiac death
Cardiovascular death
Sudden death
Non-fatal MI recurrence
Fatal and non-fatal MI
Cardiac event (fatal and non-fatal)
Subgroup analysis by HR
reduction tertile, P-value
for trend
Meta-regression, P-value for
slope
Per cent reduction for
10 b.p.m. reduction in HR
Odds ratio
Relative risk
Odds ratio
Relative risk
Odds ratio
Relative risk
0.017
0.002
0.090
0.005
0.033
0.360
—
0.015
0.002
0.110
0.005
0.030
0.320
—
0.008
,0.001
0.550
0.015
0.024
0.960
—
0.008
,0.001
0.570
0.016
0.020
0.990
—
21
33
—
41
22
—
—
20
30
—
39
21
—
—
20.0204 is similar to the one observed with the cardiac deaths
20.0396. Moreover, the relationship could have been weakened by the adding of the vascular deaths (including among
others fatal stroke) not inﬂuenced by the HR.
The meta-regression was undertaken using the odds ratio
for statistical reasons. The odds ratio has symmetric properties that the relative risk does not have; therefore, odds
ratio is more appropriate to use for a meta-regression than
the relative risk. However, in practice, it appears that the
relative risk is more relevant for clinicians (among others)
than odds ratio.23,24 The analyses carried out on relative
risk gave consistent results with analyses performed on
odds ratio. For the sake of simplicity, the relative risk can
be used to report the ﬁndings for this meta-regression.
Our results are consistent with those obtained by
Kjekshus14,25 in 1986 (updated in 1999) when considering
only beta-blockers. Our results are not simply the replication of these previous ones, given that ﬁve additional betablocker trials were added and that the focus was widened to
the other drugs modifying HR.
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Figure 6 By tertiles subgroup analysis and meta-regression for non-fatal myocardial infarction recurrence. Odds ratios represented are comparing odds between
the active treatment and placebo group.
3018
Supplementary material
Supplementary material is available at European Heart
Journal online.
Acknowledgement
We thank D. Lebrasseur, I.R.I.S and the scientiﬁc documentation
department of I.R.I.S. for their help in bibliographic searching.
Conﬂict of interest: M.C. has received research support from and is
a consultant to Servier.
Funding
This study was supported by an unrestricted grant from Servier, Inc.
The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or in the writing of the
report.
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In previous meta-analyses, only the intrinsic sympathomimetic activity has been identiﬁed as a potential effect modiﬁer of the beta-blockers beneﬁt26,27 and could be, thereby, a
confounding factor for the relation between resting HR
reduction and beneﬁt. However, a main consequence of the
intrinsic sympathomimetic activity is a low reduction in
resting HR. In fact, the relation between resting HR reduction
and beneﬁt could explain the trend towards a decreased
beneﬁt with drugs with intrinsic sympathomimetic activity.
Some potential limitations must be discussed. Data dredging is the main pitfall in reaching reliable conclusion from
meta-regression.28 Here, it can be discarded because the
covariate was pre-speciﬁed. Clearly, this work is hypothesis
testing and not exploratory like an intensive search among a
large collection of candidate covariables would be.
These results are quite robust. The relationship is found
with robust subgroup analysis that did not require strong
statistical assumptions. Moreover, the validity of these
observations is strengthened by the robustness of the sensitivity analyses and by the very good ﬁtting with the absence
of residual heterogeneity.
The relationship with resting HR lowering may be potentially confounded by other trials, drugs, or patients characteristics. Given the relatively small number of trials
reporting resting HR reduction, multivariate analyses are
not feasible in this analysis based on summary data for
each considered trials. Blood pressure reduction is a candidate confounding factor as it is probable that blood pressure
lowering induced by these drugs is in part correlated with
the induced resting HR reduction. Despite that statistical
adjustment was not feasible, it is improbable that the
found relationships were confounded by blood pressure
change. In randomized trials, clinical beneﬁt of blood
pressure lowering needed several years to appear and mortality reductions were smaller than those observed in the
present post-MI trials.29 Moreover, in the trials used in this
meta-regression, patients were included irrespective to
the presence of a hypertension.
The between trial heterogeneity concerning drugs and
patients is taken into account with the use of a random
effect model. The absence of heterogeneity does not
resolve by itself the confounding concern but gives some
reassurance that the extent of resting HR lowering is a
strong marker of clinical beneﬁt in the trials.
An interesting result of this meta-regression is the absence
of residual heterogeneity that could be interpreted as all the
beneﬁt is brought by resting HR reduction without any other
mechanism. This attractive interpretation is limited as it
derives from non-statistically signiﬁcant results. However, it
is at least reasonable to conclude that the available data
do not permit to exclude that the HR reduction is the
major determinant of the beneﬁt of drugs like beta-blockers
or calcium blockers in post-MI.
In conclusion, in post-MI condition, this meta-regression of
randomized clinical trials robustly suggests that the beneﬁt
of drugs modifying HR is strongly related to the magnitude of
reduction in resting HR. This implies that whatever the
mechanism leading to the decrease in resting HR, a same
reduction could result in the same morbidity and mortality
reduction. Each 10 b.p.m. reduction in resting HR is estimated to reduce the relative risk of cardiac death by
about 30%, the risk of sudden death by 39%, leading to a
reduction in the relative risk of all-cause mortality of 20%.
M. Cucherat
3019
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Relationship between resting HR and magnitude of clinical beneﬁts